WO2012103783A1 - Utilisation de dérivés d'artémisine et sels pharmaceutiques de ceux-ci - Google Patents

Utilisation de dérivés d'artémisine et sels pharmaceutiques de ceux-ci Download PDF

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Publication number
WO2012103783A1
WO2012103783A1 PCT/CN2012/070401 CN2012070401W WO2012103783A1 WO 2012103783 A1 WO2012103783 A1 WO 2012103783A1 CN 2012070401 W CN2012070401 W CN 2012070401W WO 2012103783 A1 WO2012103783 A1 WO 2012103783A1
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Prior art keywords
cells
leukemia
aml
kasumi
acute
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PCT/CN2012/070401
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English (en)
Chinese (zh)
Inventor
糜坚青
李英
彭宇
张瑜
聂瑞敏
刘静静
王瑾
王月英
蔡循
李阳
陈赛娟
王振义
Original Assignee
上海交通大学医学院附属瑞金医院
中国科学院上海药物研究所
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Priority to US13/982,684 priority Critical patent/US20130317095A1/en
Publication of WO2012103783A1 publication Critical patent/WO2012103783A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid

Definitions

  • the invention belongs to the field of medicine, in particular to the application of an artemisinin derivative and a pharmaceutically acceptable salt thereof.
  • Leukemia is a malignant tumor of the blood system. It is a malignant clonal disease of hematopoietic stem cells, which seriously endangers human health.
  • acute leukemia is a rapidly developing disease that causes a large accumulation of immature blood cells in bone marrow and blood, including acute non-lymphocytic leukemia (ANLL) and acute lymphocytic leukemia (ALL).
  • ANLL acute non-lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • Acute myelocytic leukemia or acute non-lymphocytic leukemia (ANLL) includes all non-lymphocytic-derived acute leukemia. It is formed by mutations in pluripotent stem cells or karyotypes of slightly differentiated precursor cells. One type of disease is a clonal malignant disease of the hematopoietic system.
  • the WHO classification criteria for acute myeloid leukemia are as follows: 1.
  • AML chromosomal translocation, characterized by the production of AML1-ETO fusion gene; (2) AML with abnormal bone marrow eosinophils, inv (16) (pl3; q22) or t (16; 16) (pl3; Q22); (3) AML is accompanied by t ( 15; 17) (q22: ql2) , (PML-RAR a ) and variant; (4) AML is accompanied by l lq23
  • AML multi-lineage hematopoietic AML
  • Treatment-related AML and MDS 4. AML without further classification, the definition of most subtypes is almost the same as the corresponding disease in the FAB classification, diagnostic criteria
  • (l) AML micro-differentiation type, SPFAB classification of AML-M0 primordial cells are similar to L2 type cells under light microscope, nucleoli are obvious, cytoplasm is transparent, basophilic, no hobby Azure particles and Auer bodies.
  • Myeloperoxidase (MPO) and Sudan black B were positive ⁇ 3%. Under electron microscopy, the MPO is (+), and the myeloid markers such as CD33 or CD13 can be (+).
  • lymphoid antigens are (-), but sometimes CD7+, TdT+ ;
  • AML is not mature, classified AML-M1: undifferentiated granulocytes (type I + 11) account for 90% of bone marrow non-erythroid cells Above, at least 3% of cells are peroxidase stained (+);
  • AML has mature type, classified AML-M2: protoblasts (type I + 11) account for 30% of bone marrow non-erythroid cells ⁇ 89%, monocytes ⁇ 20%, other granulocytes >10%;
  • AML-M4 classified by SPFAB The primordial cells in the bone marrow account for more than 30% of non-erythroid cells. The granulocytes account for 30% ⁇ 80% at each stage, and mononuclear cells at each stage>20%, CD14 Positive
  • Acute monocytic leukemia classified AML-M5: primary mononuclear, young mononuclear ⁇ 30%, CD14 positive in bone marrow non-erythroid cells; (6) acute erythroleukemia, SPFAB classified AML-M6: in bone marrow Young red blood cells ⁇ 50%, non-erythroid cells primordial cells (type I+11) ⁇ 30%; (7) acute megakaryoblastic leukemia, SPFAB classified AML-M7: primitive megakaryocytes in bone marrow ⁇ 30%, CD41, CD6 nCD42 is positive.
  • the object of the present invention is to provide an artemisinin derivative, artemisinylamine and a pharmaceutically acceptable salt thereof, and provide a novel therapeutic drug for leukemia patients.
  • the artemisinin derivative of the present invention is an artemisinyl ether amine having the following structure:
  • the inventive artemisinin derivative arsenic ether and its pharmaceutically acceptable salt can be used for preparing a medicament for treating leukemia, in particular for preparing a medicament for treating acute leukemia, more particularly for preparing acute myeloid leukemia for treatment.
  • Drug a pharmaceutically acceptable salt for preparing a medicament for treating leukemia, in particular for preparing a medicament for treating acute leukemia, more particularly for preparing acute myeloid leukemia for treatment.
  • the acute myeloid leukemia comprises reproducible genetics AML in abnormal AML is associated with t (8; 21 ) (q22; q22), (AML1/ETO) subtype and AML with t ( 15; 17) (q22: ql2) , (PML-RAR a ) subtype And AML-M2 subtypes and AML-M5 subtypes in AML not otherwise classified.
  • Figure 1 is a graph showing the growth inhibition curves of acute myeloid leukemia cells treated with SM1044, wherein (a) is Kasumi-1 cells; (b) is NB4-R1 cells; (c) is HL60 cells; (d) U937 cells.
  • Figure 2 is a graph showing the apoptosis rate of acute myeloid leukemia cells treated with SM1044 by flow cytometry, wherein (a) is Kasumi-1 cells; (b) is NB4-R1 cells; (c) is HL60 Cells; (d) U937 cells.
  • Figure 3 is a flow cytometry analysis of mitochondrial transmembrane potential of acute myeloid leukemia cells treated with SM1044, wherein (a) is Kasumi-1 cells; (b) is NB4-R1 cells; (c) HL60 cells; (d) U937 cells.
  • Figure 4 is a diagram showing the results of apoptosis-related proteins in acute myeloid leukemia cells treated with SM1044 by Western blot, wherein (a) is NB4-R1 cells; (b) is HL60 cells; (c) is U937 cells.
  • Fig. 5A is an electrophoresis pattern of SM1044-induced Kasumi-1 cell fusion protein AML1-ETO degradation assay
  • Figure 5B is an electropherogram showing SM1044-induced changes in Kasumi-1 cell fusion protein AML1-ETO at mRNA levels.
  • Figure 6 is a diagram showing the results of western blot analysis of the expression of highly expressed oncogenes in c-myc ⁇ 3 ⁇ 4 HL60 cells treated with SM1044 in HL60 cells.
  • Figure 7 is a graph showing the cell cycle results of SM1044 block acute myeloid leukemia, wherein (a) is Kasumi-1 cells; (b) is HL60 cells.
  • Figure 8 is a graph showing the growth curve of SM1044 inhibiting acute myeloid leukemia cell xenografts in mice, wherein (a) is Kasumi-1 cells; (b) is HL60 cells; (c) is U937 cells. detailed description The present invention will be further described below in conjunction with specific embodiments. It is to be understood that the following examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the cell lines used in the following examples were derived from the Shanghai Blood Institute and included the following cell lines:
  • Kasumi-1 cells are AML with t (8; 21 ) (q22; q22), (AML1/ETO) subtype cell line, NB4-R1 cells are AML with t ( 15; 17) (q22: ql2), (PML-RAR a ) subtype retinoic acid resistant cell line, HL60 cell is AML-M2 subtype cell line, and U937 cell is AML-M5 subtype cell line.
  • Example 1 Preparation of artemisinin derivative arsenic ether amine maleate
  • This example is prepared from the known compound hydroxyethyl ether (Reference: Li Ying et al., Pharmacological Journal, 1981, 16: 429-439), which is first prepared with p-toluenesulfonate and then in solvent dimethylformamide. The reaction with ammonia water gives the artemisinyl ether amine.
  • the reaction route is:
  • the resulting artemisinide amine is then reconstituted into the maleate salt.
  • SM1044 was first dissolved in tri-distilled water at a concentration of 1 mg/ml, and then the typical acute myeloid leukemia cell lines Kasumi-1, NB4-K HL60 and U937 cells were selected for experiments.
  • a blank group, a non-medicated control group, and different concentration dosing groups were set, and three parallel holes were set for each concentration.
  • MTT (5 mg/ml) was added and culture was continued for 4 h.
  • IC 5Q was 0.17 ⁇ (Kasumi-1 cells, Figure 1 (a)), 0.021 ⁇ (NB4-R1 cells, Figure 1 (b) )), 0.04 ⁇ (HL60 cells, Figure 1 (c)), 0.02 ⁇ (U937 cells, Figure 1 (d)), indicating that SM1044 can inhibit leukemic cell proliferation.
  • Kasumi-1, NB4-K HL60 and U937 cells were seeded in cell culture dishes at a concentration of 3 x 10 5 to 5 x 10 5 /ml.
  • the control group (0 ⁇ ) and the different concentrations of the drug-added groups were separately cultured for 24 h and 48 h, and the cells to be detected were collected.
  • the cells were washed twice with pre-cooled phosphate buffer (PBS) and then mixed with 200 ⁇ l of binding buffer (binding buffer). Resuspend, add 5 ⁇ ⁇ V-FITC and 5 ⁇ propidium iodide ( ⁇ ), mix gently, incubate at room temperature for 15 min in the dark, and measure by flow cytometry in lh.
  • PBS pre-cooled phosphate buffer
  • binding buffer binding buffer
  • SM 1044 acted on Kasumi-1 (Fig. 2 (a)), NB4- 1 (Fig. 2 (b)), HL60 (Fig. 2 (c)) and U937 cells (Fig. 2 (d)).
  • Apoptosis can be induced within ⁇ 48 hours. It indicated that SM1044 could induce apoptosis of leukemia cells, and the proportion of apoptotic cells increased with the increase of drug concentration and prolongation of treatment time.
  • Example 4 SM1044 leukemia cells induced loss of mitochondrial transmembrane potential Assay Kasumi-1, NB4- K HL60 and U937 cells 3x l0 5 ⁇ 5x l0 5 cells / ml were seeded in cell culture dishes.
  • the control group (0 ⁇ ) and the different concentration dosing groups were set up, cultured for 24 h and 48 h, respectively, and 20 nM DiOC 6 (3) was added at 37 ° C for 15 min in the dark, and the cells were washed twice with PBS. The cells were resuspended in 100 ⁇ PBS and detected by flow cytometry.
  • DiOC 6 (3)-negative cells are cells in which the mitochondrial transmembrane potential is lost.
  • SM1044 makes Kasumi-1 (Fig. 3 (a) and Table 1), NB4- 1 (Fig. 3 (b) and Table 2), HL60 (Fig. 3 (c) and Table 3) and U937 (Fig. 3 (d) ) and Table 4) Loss of mitochondrial transmembrane potential in cells, while potential loss is time- and concentration-dependent. Apoptosis includes both intrinsic pathways and extrinsic pathways. The loss of mitochondrial transmembrane potential is an important manifestation of the intrinsic pathway of apoptosis. The results indicate that SM 1044 can induce the apoptosis of Kasumi-1, NB4-K HL60 and U937 cells through the intrinsic pathway. Die.
  • Example 5 SM1044 induces apoptosis-related protein formation in leukemia cells
  • NB4-R1, HL60 and U937 cells were seeded in cell culture dishes at a concentration of 3 x 10 5 to 5 x 10 5 /ml.
  • the control group (0 ⁇ ) and the different concentrations of the drug-added group were set up, and the total protein was extracted after 24 hours of culture.
  • the anti-apoptosis-related proteins (PARP, caspase-3, caspase-8, caspase-9) were obtained by western blot.
  • the antibody detects changes in the amount of apoptosis-related proteins.
  • the Caspase family plays a very important role in mediating apoptosis.
  • apoptosis There are two main pathways for apoptosis: one is to activate the cell's apoptotic enzyme caspase-8 by extracellular signal; the other is to activate caspase-9 by releasing mitochondrial apoptotic enzyme activator. These activated caspases in turn activate the apoptosis-executing protein caspase-3, which is a substrate for caspase-3.
  • caspase-3 and caspase were activated by apoptosis-related proteins in NB4-R1 (Fig. 4 (a)), HL60 (Fig. 4 (b)) and U937 (Fig. 4 (c)) cells after treatment with SM1044.
  • SM1044 induced Kasumi-1 cell fusion protein AML1-ETO degradation assay 1 ⁇ 10 7 Kasumi-1 cells were suspended in 20 ml of medium and seeded in a cell culture dish. The control group (Con) and the different concentration dosing groups were set separately. After 24 h of culture, the total rnRNA was extracted, and the change of the fusion protein at the mRNA level was detected by RT-PCR. As shown in Fig. 5A, the results showed that SM1044 did not affect the fusion gene. Transcription of AML1-ETO.
  • Kasumi-1 cells were then seeded in cell culture dishes at a concentration of 5 x 105/ml.
  • the control group (Con) and the different concentration dosing groups were set separately.
  • the total protein was extracted, and the change of the fusion protein AML1-ETO was detected by Western blot, as shown in Fig. 5B. It indicates that SM1044 degrades the fusion protein AML1-ETO, and when the concentration of SM1044 is 1 ⁇ , the degradation of the fusion protein AML1-ETO can be induced.
  • the fusion protein AML1-ETO which is a characteristic fusion gene of AML-M2b, plays an important role in the development of leukemia and can be used as a target for drug action.
  • the results of this study showed that SM1044 can significantly degrade the fusion protein AML1-ETO, indicating that the fusion protein AML1-ETO can be used as an intracellular target for SM1044.
  • Example 7 SMI 044 inhibits oncogene c-myc expression in HL60 cells HL60 cells were seeded in cell culture dishes at a concentration of 3 x 105/ml. The control group (0 ⁇ ) and the different concentration dosing groups were set up. After 24 hours of culture, the total protein was extracted.
  • oncogene c-myc was detected by anti-c-myc antibody by western blot.
  • One of the hallmarks of HL60 cells is the high expression of the oncogene c-myc.
  • Figure 6 when the concentration of SM1044 is greater than 1 ⁇ , it can completely inhibit the expression of the oncogene c-myc in HL60 cells, indicating that SM1044 is on the oncogene c.
  • the expression of -myc has an inhibitory effect.
  • Example 8 SM1044 block leukemia cell cycle test
  • Kasumi-1 and HL60 cells were seeded in cell culture dishes at a concentration of 5 x 10 5 /ml.
  • the control group (Con) and the different concentration dosing groups were set separately.
  • the cells were collected, washed twice with PBS, and fixed with 70% cold ethanol at 4 ° C overnight.
  • the cells were washed with PBS, resuspended in PBS containing 10 mg/ml RNase, incubated at 37 °C for 30 min, and then added with 50 ⁇ M ⁇ propidium iodide ( ⁇ ) for DNA staining. Flow cytometry within 1 h. Analyze the distribution of cellular DNA content.
  • Example 9 SM1044 inhibits mouse leukemia cell xenograft growth test
  • mice model of acute myeloid leukemia cell line Kasumi-1, HL60 and U937 cells was established, subcutaneously injected with lx lO 7 leukemia cells, the mice grew to a length of about 5 mm, and the mice were divided into two groups, respectively Control group (Con), different concentrations of the drug group. Each day, the intraperitoneal injection was 0.125 ml (Kasumi-1 and HL60 cells) or 0.1 ml (U937 cells), and the control group was injected with the same amount of normal saline for 18 to 35 days. The mouse mass was measured daily. . The results showed that in the mouse xenograft model of Kasumi-1 (Fig. 8 (a)), HL60 (Fig.
  • Artemisinin is a sesquiterpene lactone with a peroxy group extracted from the plant Artemisia annua L., artesunate, artemether and dihydroartemisinin. ) are all derivatives of artemisinin. At present, the above artemisinin drugs have become the first line of drugs for the treatment of malaria worldwide.
  • SM1044 can inhibit leukemia cell proliferation and induce apoptosis, with time and dose. Dependence. SM1044 can be used for the preparation of drugs for the treatment of leukemia, especially for the treatment of acute leukemia, more particularly for the preparation of drugs for the treatment of acute myeloid leukemia.
  • the artemisinin derivative of the invention has a strong ability to induce apoptosis of leukemia, and can inhibit tumor cells in a short time and a small dose, and has less toxic and side effects, and has important significance for clinical treatment of leukemia.

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Abstract

La présente invention concerne l'utilisation de dérivés d'artémisine et des sels pharmaceutiques de ceux-ci. Les dérivés d'artémisine, (dimère d'arteéther)amine, et les sels pharmaceutiques de ceux-ci peuvent inhiber la prolifération de cellules leucémiques, bloquer le cycle de cellules leucémiques, et induire l'apoptose de cellules leucémiques. Les dérivés d'artémisine, (dimère d'arteéther)amine, et les sels pharmaceutiques de ceux-ci dans la présente invention peuvent être utilisés pour fabriquer des médicaments dans le traitement de la leucémie, en particulier dans le traitement d'une leucémie aiguë, plus particulièrement dans le traitement de la leucémie myéloïde aiguë.
PCT/CN2012/070401 2011-01-31 2012-01-16 Utilisation de dérivés d'artémisine et sels pharmaceutiques de ceux-ci WO2012103783A1 (fr)

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CN201110034201.X 2011-01-31
CN201110034201XA CN102614168A (zh) 2011-01-31 2011-01-31 一种青蒿素衍生物及其药用盐的应用

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CN103202837B (zh) * 2012-01-16 2015-05-13 上海交通大学医学院附属瑞金医院 青蒿素衍生物及其药用盐用于治疗制备白血病的药物
CN103202836B (zh) * 2012-01-16 2015-05-13 上海交通大学医学院附属瑞金医院 青蒿素衍生物及其药用盐用于制备治疗急性髓细胞性白血病的药物
CN103202835B (zh) * 2012-01-16 2015-05-13 上海交通大学医学院附属瑞金医院 青蒿素衍生物及其药用盐用于制备治疗急性白血病的药物
GB201800736D0 (en) * 2018-01-17 2018-02-28 St Georges Hospital Medical School Combination therapy for treatment of leukemia

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CN101421276A (zh) * 2006-04-11 2009-04-29 赛诺菲-安万特 青蒿素衍生物的二聚物，它们的制备与它们的治疗应用
CN102153564A (zh) * 2011-01-31 2011-08-17 中国科学院上海药物研究所 含氮原子的青蒿素二聚体、其制备方法及用途

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US5677468A (en) * 1995-06-29 1997-10-14 Hauser, Inc. Artemisinin dimer compounds having anticancer activity

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Publication number Priority date Publication date Assignee Title
CN101421276A (zh) * 2006-04-11 2009-04-29 赛诺菲-安万特 青蒿素衍生物的二聚物，它们的制备与它们的治疗应用
CN102153564A (zh) * 2011-01-31 2011-08-17 中国科学院上海药物研究所 含氮原子的青蒿素二聚体、其制备方法及用途

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